The first 17 amino acids of huntingtin (NT17 domain) has been implicated as a critical regulator of mutant huntingtin (mhtt) mediated disease pathogenesis in Huntington's disease (HD). In the current study, we created a novel BAC mouse model of HD expressing full-length mhtt lacking this domain (BACHD-dNT17), and showed that these mice exhibit accelerated nuclear mhtt accumulation (hence supporting its role as a cytoplasmic retention signal in vivo), and exacerbate HD-like disease pathogenesis including movement disorder and striatal neurodegeneration. Based on these exciting findings, we hypothesize that the NT17 domain and its cytoplasmic interactors are critical in preventing mhtt nuclear accumulation and HD-like disease pathogenesis in vivo. To test this hypothesis, we proposed the following two Aims: Aim One. Using independent transgenic mouse lines to show the NT17 domain can prevent nuclear mhtt accumulation and HD-like disease pathogenesis in a polyQ-length dependent manner in vivo. Aim Two. Validating novel NT17 interacting proteins as cytoplasmic acceptors that mediate NT17- dependent htt cytoplasmic retention in cell models, and one such interactor, Tcp1, as modifier of HD pathogenesis in vivo. Our study may provide novel therapeutic insights based on the NT17 domain and its interacting proteins to ameliorate nuclear mhtt toxicity and prevent the onset of movement disorder and neurodegeneration in HD. PUBLIC HEALTH RELEVANCE: Huntington's disease (HD) is a common inherited fatal neurodegenerative disorder that is characterized by progressive motor, cognitive, and psychiatric symptoms. Our proposed study is based on the surprising finding that deletion of the first 17 amino acids of mutant huntingtin (NT17 domain) leads to accelerated nuclear mutant huntingtin accumulation and triggers HD-like movement disorder and neurodegeneration. Elucidating the precise underlying molecular mechanisms through which the NT17 domain and its molecular interactors can suppress HD pathogenesis in mouse genetic models may provide novel therapeutic targets for HD.